The role of a FAD cofactor in the regulation of acetohydroxyacid synthase by redox signaling molecules

Lonhienne, Thierry, Garcia, Mario D. and Guddat, Luke W. (2017) The role of a FAD cofactor in the regulation of acetohydroxyacid synthase by redox signaling molecules. Journal of Biological Chemistry, 292 12: 5101-5109. doi:10.1074/jbc.M116.773242

Author Lonhienne, Thierry
Garcia, Mario D.
Guddat, Luke W.
Title The role of a FAD cofactor in the regulation of acetohydroxyacid synthase by redox signaling molecules
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2017-03-24
Sub-type Article (original research)
DOI 10.1074/jbc.M116.773242
Open Access Status Not yet assessed
Volume 292
Issue 12
Start page 5101
End page 5109
Total pages 9
Place of publication Rockville, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
Abstract Acetohydroxyacid synthase (AHAS) catalyzes the first step of branched-chain amino acid (BCAA) biosynthesis, a pathway essential to the lifecycle of plants and microorganisms. This enzyme is of high interest because its inhibition is at the base of the exceptional potency of herbicides and potentially a target for the discovery of new antimicrobial drugs. The enzyme has conserved attributes from its predicted ancestor, pyruvate oxidase, such as a ubiquinone-binding site and the requirement for FAD as cofactor. Here, we show that these requirements are linked to the regulation of AHAS, in relationship to its anabolic function. Using various soluble quinone derivatives (e.g. ubiquinones), we reveal a new path of down-regulation of AHAS activity involving inhibition by oxidized redox-signaling molecules. The inhibition process relies on two factors specific to AHAS: (i) the requirement of a reduced FAD cofactor for the enzyme to be active and (ii) a characteristic slow rate of FAD reduction by the pyruvate oxidase side reaction of the enzyme. The mechanism of inhibition involves the oxidation of the FAD cofactor, leading to a time-dependent inhibition of AHAS correlated with the slow process of FAD re-reduction. The existence and conservation of such a complex mechanism suggests that the redox level of the environment regulates the BCAA biosynthesis pathway. This mode of regulation appears to be the foundation of the inhibitory activity of many of the commercial herbicides that target AHAS.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1008736
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
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